Encephalitis

Encephalitis is the inflammation of brain parenchyma with neurological dysfunction. Infectious encephalitis is caused by viral (most common), bacterial, parasitic, or fungal pathogens. Autoimmune encephalitis is associated with the production of autoantibodies to neuronal antigens and is often paraneoplastic. Prodromal symptoms include fever, headache, and nausea, with progression to neurological and psychiatric symptoms within hours to weeks, including altered mental status, seizures, focal neurological deficits, hallucinations, and psychosis. Diagnosis is based on laboratory studies (serology, CSF analysis) and brain MRI. Initial testing includes serum and CSF tests for common and treatable causes of encephalitis. Additional testing is guided by clinical features and epidemiological clues (e.g., season, geographic location, travel, and exposure history). Evaluation for malignancy is indicated in all patients with proven or suspected autoimmune encephalitis. Brain biopsy may be considered if the cause of encephalitis remains unknown. Empiric antimicrobial therapy for encephalitis is initiated immediately in all patients and always includes IV acyclovir. Empiric antibiotic therapy for bacterial meningitis and doxycycline to cover for tick-borne infections may be added based on clinical suspicion. Antimicrobial therapy is tailored once an infectious cause has been identified. Immunomodulatory treatment for autoimmune encephalitis may be considered once infectious causes have been excluded.

• Encephalitis: inflammation of brain parenchyma with neurological dysfunction
  • Cerebellitis: inflammation of the cerebellum
  • Brainstem encephalitis: inflammation of the brainstem and adjacent regions
• Meningoencephalitis: concurrent inflammation of meninges (meningitis) and brain parenchyma (encephalitis)
• Encephalomyelitis: concurrent inflammation of the brain (encephalitis) and spinal cord (myelitis)

There is substantial overlap in the clinical features of encephalitis from different causes. See “Diagnosis of encephalitis” and “Management of encephalitis” for the initial approach to all patients.

Consult infectious diseases and begin empiric antimicrobial therapy for encephalitis without delay until a treatable infectious cause of encephalitis is ruled out.

Treat acute seizures and begin management of elevated intracranial pressure during the primary survey.

• Progression: acute (hours to days) or subacute (days to weeks)
• Nonspecific prodromal symptoms (hours to weeks prior)
  • Fever
  • Headache
  • Nausea
• Neurological
  • Altered mental status
  • Memory loss
  • Seizures (focal or generalized)
  • Focal neurological deficits
    • Hemiparesis
    • Hyperreflexia
    • Cranial nerve palsies
    • Language dysfunction (e.g., aphasia, dysarthria)
    • Extrapyramidal symptoms
  • Dysautonomia
• Psychiatric
  • Behavioral changes (e.g., hypersexuality, hypomania, agitation)
  • Hallucinations
  • Anxiety
  • Psychosis

Subacute onset of psychiatric symptoms in combination with seizures and/or focal neurological deficits should raise clinical suspicion for encephalitis.

Suspect encephalitis in any patient with altered mental status of unknown cause.

Approach ^[1][2][4]

• Clinical evaluation
  • Evaluate for clinical features of encephalitis and perform a thorough neurological examination.
  • Identify risk factors for infectious encephalitis.
  • Identify causes of autoimmune encephalitis, e.g., underlying malignancy.
  • Identify clinical features of underlying conditions (see “Overview of encephalitis”).
  • Exclude differential diagnoses of encephalitis.
• Initial investigations (all patients)
  • Routine laboratory studies (CBC, CMP, blood cultures) and HIV testing
  • Lumbar puncture (LP) if no contraindications to LP ^[4]
  • Brain imaging (ideally MRI with IV contrast)
  • EEG
  • Serum and CSF tests for common and treatable causes of encephalitis
• Additional investigations
  • Freeze CSF samples for further testing.
  • Consult infectious diseases and neurology for guidance on additional investigations for encephalitis.

Do not delay empiric treatment; initiate diagnostic and treatment steps in parallel.

Initial laboratory studies ^[1][2][3]

Routine tests

• Basic blood tests: CBC, coagulation panel, CMP
• HIV testing (e.g., fourth-generation HIV test): Obtain in all patients. ^[4]
• CSF analysis
  • Typical findings in viral and autoimmune encephalitis
    • Opening pressure: may be normal or elevated ^[6]
    • Cell count: WBC > 5/mm³; typically increased lymphocytes (lymphocytic pleocytosis)
    • Protein: normal to moderately increased
    • Glucose: normal (approx. two-thirds of blood glucose level)
  • See also “CSF analysis in meningitis” and “CSF analysis in HSV encephalitis.”

A normal CSF analysis does not exclude encephalitis. ^[1]

Infectious and immune studies ^[2]

Studies include initial universal testing for common and treatable causes of encephalitis. ^[2][3]

• Studies in blood and serum
  • Blood cultures (two sets): Obtain before starting antibiotic therapy.
  • Serological studies for syphilis: e.g., RPR or treponemal testing
  • West Nile virus IgM antibody (seasonal)
  • Anti-NMDAR antibodies
  • Serum IgG
  • Residence in or travel to endemic areas: serological testing for Borrelia, Rickettsia, Ehrlichia, and Anaplasma species
• Studies in CSF
  • CSF cultures and Gram stain
  • PCR
    • Single viral PCR tests for HSV-1, HSV-2, VZV, and enteroviruses ^[2]
    • Or, if available, multiplex PCR meningitis/encephalitis panel
  • Tests for other infections: VDRL, cryptococcal antigen, West Nile virus IgM antibody (seasonal) ^[2]
  • Tests for autoimmune encephalitis: anti-NMDAR antibodies, IgG index, oligoclonal bands
• Additional studies in children < 18 years of age ^[2]
  • Mycoplasma pneumoniae serology: IgG and IgM antibodies
  • EBV serology: anti-VCA IgM and IgG antibodies, anti-EBNA IgG
  • Throat or oropharyngeal swabs: multiplex PCR for respiratory pathogens
  • Stool or rectal swabs: enteroviral PCR

CSF PCR may be falsely negative early in the course of HSV encephalitis. If no pathogen is identified on initial testing, check HSV PCR on a repeat CSF sample after 3–7 days. ^[2]

Neuroimaging ^[1][2]

• Brain MRI with contrast: imaging modality of choice ; ^[1]
  • Indicated in all patients with suspected encephalitis
  • Findings and pattern of neuroradiologic involvement may suggest specific causes, e.g.: ^[2]
    • Temporal lobes: HSV encephalitis, limbic encephalitis
    • Basal ganglia, thalamus: West Nile encephalitis, Japanese encephalitis
    • Brain stem: Listeria encephalitis, enteroviral encephalitis
    • Cerebellum: VZV, EBV
    • White matter lesions: acute disseminated encephalomyelitis
    • Ischemic lesions: VZV, syphilis, fungal infections, tuberculosis
• Brain CT (with and without contrast): if MRI is contraindicated or not available ^[1]

Always consider HSV encephalitis if imaging shows temporal lobe involvement; bilateral temporal lobe abnormality is pathognomonic. ^[1]

A normal brain MRI does not exclude encephalitis.

EEG ^[1][3]

• Indication: suspected encephalitis (all patients)
• Findings: usually nonspecific
  • Epileptiform discharges from the affected temporal lobes in HSV encephalitis
  • Extreme delta brush in anti-NMDA encephalitis

EEG can identify nonconvulsive status epilepticus as a cause of altered mental status.

Additional investigations for encephalitis ^[1][2][3]

Additional testing is guided by infectious diseases and neurology based on clinical features, exposures, risk factors, and local epidemiology.

• Serum and CSF tests: often performed on prefrozen samples if initial testing is negative
  • Infectious causes of encephalitis: testing for additional opportunistic, seasonal, and/or locally endemic infections
  • Autoimmune causes of encephalitis: testing for additional autoantibodies
  • Other disorders: CSF cytology and flow cytometry, testing for prion disease (e.g., RT-QuIC)
• Other tissue and/or fluid sampling: e.g., for culture, PCR, histology
  • Upper respiratory illness: throat swabs
  • Pulmonary involvement: sputum and/or bronchoalveolar lavage
  • Rash: biopsy
  • Diarrhea: stool studies
• Malignancy evaluation: See “Diagnostics” in “Autoimmune encephalitis.”
• Brain biopsy: considered if the cause of encephalitis remains unknown and the patient is clinically deteriorating

See also “Causes of AMS and coma,” “Causes of agitation,” and “Etiology of delirium.”

• Encephalopathies
  • Metabolic encephalopathies: e.g., uremic encephalopathy, hepatic encephalopathy, Hashimoto encephalopathy
  • HIV encephalopathy
  • Wernicke encephalopathy
  • Multicystic encephalopathy
  • Hypertensive encephalopathy
  • Chronic toxic encephalopathy
  • Wilson disease
  • Anoxic encephalopathy
  • Neonatal encephalopathy
• Vascular disorders: e.g., stroke, thrombosis
• Degenerative disorders: e.g., Alzheimer disease, frontotemporal dementia, Prion disease
• Neuropsychiatric disorders: psychosis, Huntington disease
• Other conditions
  • Meningitis
  • Epilepsy
  • Substance intoxication or withdrawal

The differential diagnoses listed here are not exhaustive.

Encephalitis is a life-threatening disease with nonspecific clinical presentation; treatment delays result in poor outcomes.

Approach ^[1][2]

• Acutely ill patients: Follow the ABCDE approach.
  • Airway management and ventilation (e.g., if GCS is < 8)
  • Immediate hemodynamic support
  • Management of agitation
  • Initial stabilization for acute seizures
  • Management of elevated intracranial pressure (ICP)
• All patients
  • Consult neurology and infectious diseases immediately.
  • Initiate immediate empiric antimicrobial therapy for encephalitis before diagnostic confirmation.
  • Once etiology is known, tailor cause-specific management under specialist guidance.
  • See “Treatment” in “Infectious encephalitis” and “Autoimmune encephalitis” for details.
• Disposition ^[7]
  • Admit to the hospital for multidisciplinary care.
  • Consider neurological ICU admission for severely ill patients (e.g., with seizures, signs of elevated ICP).

Empiric antimicrobial therapy for encephalitis ^[1][2]

• All patients: Start antimicrobial treatment for HSV encephalitis with IV acyclovir. ^[1][2]
• Possible bacterial meningitis: Add empiric antibiotic therapy for bacterial meningitis. ^[1][2]
• Possible rickettsiosis or ehrlichiosis: Add doxycycline (off-label for ehrlichiosis and for children < 8 years of age). ^[1][2][8]

CSF HSV-1 PCR may be falsely negative early in the disease course. If clinical suspicion of HSV encephalitis persists despite an initial negative result, continue IV acyclovir and repeat testing after 3–7 days. ^[2]

Empiric immunomodulatory therapy for autoimmune encephalitis ^[9]

• Consider after infectious causes have been excluded.
• See “Treatment of autoimmune encephalitis.”

• Follow the ABCDE approach.
• Manage acute seizures
• Manage elevated ICP.
• Obtain personal and exposure history.
• Perform a comprehensive physical examination.
• Obtain initial diagnostics.
  • Routine laboratory studies (CBC, CMP, blood cultures) and HIV testing
  • Lumbar puncture if no contraindications to LP
  • Neuroimaging (ideally MRI brain with IV contrast)
  • EEG
• Send tests for common and treatable causes of encephalitis.
• Consult infectious diseases and neurology.
• Begin initial management of encephalitis, including empiric antimicrobial therapy for encephalitis.
• Admit to hospital; consider ICU admission for severely ill patients.
• Initiate cause-specific treatment after diagnostic confirmation.

Etiology of infectious encephalitis ^[1][2]

Viral encephalitis

Viral encephalitis is the most common type of infectious encephalitis.

• Herpesviruses
  • Herpes simplex virus type 1 (HSV-1): HSV encephalitis (most common cause of encephalitis)
  • Herpes simplex virus type 2 (HSV-2): HSV encephalitis (in neonates and the immunocompromised)
  • Varicella zoster virus (VZV): herpes zoster encephalitis ^[2]
  • Cytomegalovirus (CMV): CMV encephalitis (most commonly affects immunocompromised individuals, especially those with AIDS)
  • Epstein-Barr virus (EBV): EBV encephalitis (most commonly affects children, adolescents, and immunocompromised individuals) ^[2][3]
• Mosquito-borne viruses
  • West Nile virus: West Nile encephalitis
  • Murray Valley encephalitis virus: Murray Valley encephalitis
  • Japanese encephalitis virus: Japanese encephalitis
  • St. Louis encephalitis virus: St. Louis encephalitis
  • Western equine encephalitis virus: western equine encephalitis
  • Eastern equine encephalitis virus: eastern equine encephalitis
  • La Crosse virus: La Crosse encephalitis
  • California encephalitis virus: California encephalitis ^[10]
• Tick-borne viruses
  • Tick-borne encephalitis virus: tick-borne encephalitis
  • Powassan virus: Powassan encephalitis
  Other
  • Enteroviruses: enteroviral encephalitis
  • Human immunodeficiency viruses (HIV): HIV-associated neurocognitive disorder, acute retroviral syndrome
  • Measles virus: encephalitis, subacute sclerosing panencephalitis
  • Mumps virus: mumps encephalitis
  • Rabies virus: encephalitic rabies

Bacterial encephalitis

Bacterial encephalitis may be a primary infection or secondary to extracerebral bacterial infection.

• Treponema pallidum: neurosyphilis
• Borrelia burgdorferi: neuroborreliosis
• Listeria monocytogenes: listeria encephalitis
• Rickettsia rickettsii: Rocky Mountain spotted fever (RMSF)
• Ehrlichia: ehrlichiosis
• Mycobacterium tuberculosis: tuberculous meningoencephalitis

Fungal encephalitis

• Cryptococcus neoformans: cryptococcal meningoencephalitis
• Coccidioides spp.: coccidioidomycosis
• Histoplasma capsulatum: histoplasmosis

Parasitic encephalitis

• Toxoplasma gondii: toxoplasmic encephalitis
• Plasmodium falciparum: cerebral malaria
• Trypanosoma brucei: African trypanosomiasis
• Naegleria fowleri: primary amebic meningoencephalitis

Risk factors for infectious encephalitis ^[1][2][4]

• Travel to endemic areas
• Contact with vector animals and insects (e.g., mosquitoes, ticks)
• Recreational and occupational exposure
• Risky food exposure (e.g., unpasteurized milk or raw/undercooked meat)
• Sick contacts
• Underimmunization
• Risk factors for sexually transmitted infections
• Risk factors for HIV or other immune compromise

Clinical features

See “Clinical features of encephalitis.”

Diagnostics ^[1][2]

• See “Diagnosis of encephalitis” for a structured approach to the workup of undifferentiated encephalitis.
• Testing for universally common pathogens (e.g., HSV-1, HSV-2, VZV, enteroviruses) is recommended in all patients.
• Testing for additional pathogens is considered based on patient and epidemiological factors.

Treatment ^[1][2][3]

• Begin initial management of encephalitis.
• Administer empiric antimicrobial therapy for encephalitis.

Pathogen-specific treatment

Once the etiology of infectious encephalitis is identified, switch to tailored treatment under infectious diseases specialist guidance(see respective disease articles for dosages).

• Viral
  • Treatment of HSV encephalitis; or antiviral therapy for VZV infection: IV acyclovir
  • Treatment of CMV infection: IV ganciclovir PLUS IV foscarnet
  • HIV-associated neurocognitive disorder: antiretroviral therapy
  • Most other viruses: no specific antiviral therapy; supportive care
• Bacterial
  • Meningitis: empiric antibiotics for bacterial meningitis
  • Treatment of listeriosis: IV ampicillin PLUS IV gentamicin
  • Treatment of neurosyphilis: IV penicillin G OR IV ceftriaxone
  • TB meningoencephalitis: extended RIPE TB regimen with adjunctive glucocorticoids (See “Treatment of extrapulmonary TB” for details.)
  • See also “Pathogen-specific therapy in meningitis.”
• Tick-borne bacterial
  • Lyme neuroborreliosis: IV ceftriaxone, IV cefotaxime, OR IV penicillin G
  • RMSF or ehrlichiosis: PO/IV doxycycline
• Fungal
  • Cryptococcal meningoencephalitis: amphotericin B PLUS flucytosine
  • Coccidioides encephalitis: fluconazole, itraconazole, voriconazole, OR amphotericin B
  • Histoplasma encephalitis: amphotericin B followed by itraconazole
  • For antifungal dosages, see “Management of systemic fungal infections.”
• Parasitic
  • Treatment of cerebral toxoplasmosis: pyrimethamine PLUS sulfadiazine PLUS leucovorin ^[11]
  • Treatment of cerebral malaria: IV artesunate followed by PO artemether-lumefantrine ^[12]
  • Treatment of African trypanosomiasis: fexinidazole OR a combination of eflornithine PLUS nifurtimox ^[13]
  • Primary amebic meningoencephalitis: IV and intrathecal amphotericin B PLUS rifampin PLUS other agents ^[1][14]

Etiology ^[2][9][15]

• Paraneoplastic encephalitis: inflammation of the brain caused by an immune-mediated response to a systemic malignancy
• Nonparaneoplastic autoimmune encephalitis
  • Idiopathic
  • Postinfectious: e.g., acute disseminated encephalomyelitis, post-HSV encephalitis
  • Systemic autoimmune disorders: e.g., SLE, sarcoidosis
  • Iatrogenic: caused by immune-modulating agents, e.g., immune checkpoint inhibitors

Classification of autoimmune encephalitis ^[2][9][15]

Autoimmune encephalitis can be classified by etiology, serological findings, or affected anatomic region.

• Etiologic
  • Paraneoplastic encephalitis
  • Nonparaneoplastic autoimmune encephalitis
• Serologic
  • Autoantibody-associated encephalitis: associated with autoantibodies to neuronal intracellular antigens ; ^[9]
    • Anti-Hu antibodies: paraneoplastic brainstem encephalitis often associated with small cell lung cancer
    • Anti-Yo antibodies: paraneoplastic cerebellar encephalitis often associated with gynecologic and breast malignancies
    • Anti-Tr antibodies: paraneoplastic cerebellar encephalitis often associated with Hodgkin lymphoma
  • Autoantibody-mediated encephalitis: mediated by autoantibodies to neuronal surface antigens ; ^[9]
    • Anti-NMDAR antibodies; : paraneoplastic encephalitis (e.g., due to ovarian teratoma), post-HSV encephalitis
    • VGKC-complex antibodies: nonparaneoplastic limbic encephalitis
  • Seronegative autoimmune encephalitis: not associated with identifiable autoantibodies
• Anatomic
  • Limbic encephalitis
  • Cerebellitis
  • Brainstem encephalitis

Clinical features ^[9][16]

General clinical features of encephalitis are usually present. The following features are more suggestive of autoimmune encephalitis:

• Subacute or chronic onset
• Clinical features of underlying etiology, e.g.:
  • Malignancy, e.g., constitutional symptoms
  • Recent viral illness
  • Autoimmune disease (e.g., clinical features of SLE)
• Prominent psychiatric and neurological manifestations (e.g., in anti-NDMAR encephalitis and limbic encephalitis)

Autoimmune encephalitis cannot be distinguished from infectious encephalitis based on clinical features alone. ^[9][16]

Diagnostics ^[2][9]

See “Diagnosis of encephalitis” for a structured approach to the workup of undifferentiated encephalitis.

• Routine investigations
  • Test all patients for anti-NMDAR antibodies (in serum and CSF), IgG index, and oligoclonal bands.
  • Consider paraneoplastic panel testing in serum and CSF based on availability and local protocols.
• Further testing
  • Consider testing for additional autoantibodies in consultation with neurology.
  • See “Classification of autoimmune encephalitis” for specific antibodies.
• Evaluation for underlying malignancy: Consider in all adults with confirmed or suspected autoimmune encephalitis.
  • CT chest, abdomen, and pelvis
  • Mammography, pelvic ultrasound
  • Whole body PET-CT scan if initial evaluation is negative

Treatment of autoimmune encephalitis ^[9]

• Approach
  • For preliminary steps, see “Initial treatment of encephalitis.”
  • If clinical suspicion is high, consider empiric therapy prior to diagnostic confirmation once infectious causes are excluded. ^[9]
  • Consult a specialist (e.g., neurology) for guidance on treatment options.
  • Consider neurological ICU admission for severely ill patients (e.g., with seizures, signs of elevated ICP).
• All patients: immunomodulatory therapy
  • First-line: high-dose corticosteroids, intravenous immunoglobulin, plasmapheresis
  • Second-line: rituximab, cyclophosphamide
• Paraneoplastic encephalitis: immunomodulatory treatment and treatment of the underlying malignancy (e.g., tumor resection)

Anti-NMDA receptor encephalitis ^[2][16][17]

• Epidemiology ^[2]
  • Most common type of autoimmune encephalitis
  • Most common in children and young adults
  • ♀:♂ = 4:1
• Etiology
  • Approx. 50% of cases are paraneoplastic. ^[2]
  • Often associated with ovarian teratoma
  • May develop as a complication of HSV encephalitis ^[3][18]
• Clinical features: similar to the general clinical features of encephalitis with prominent psychiatric and neurological manifestations
  • Cognitive and behavioral abnormalities: e.g., psychosis, agitation, catatonia
  • Memory deficits
  • Speech dysfunction
  • Dyskinesias and/or seizures
  • Autonomic dysfunction
  • Decreased level of consciousness
• Diagnostics: See “Diagnosis of encephalitis” for a structured approach to the workup of undifferentiated encephalitis.
  • Confirmatory test: positive anti-NMDA receptor antibodies in CSF ^[16]
  • CSF analysis: WBC count usually < 50 WBCs/mm³
  • Brain MRI: may be normal
  • EEG
    • Slowing, epileptogenic activity
    • Extreme delta brush: a pathognomonic pattern resembling waveforms seen in premature infants
  • Malignancy evaluation: e.g., transvaginal ultrasonography to evaluate for ovarian teratoma
• Treatment
  • Immunomodulatory therapy (See “Treatment of autoimmune encephalitis.”)
  • Treatment of the underlying tumor (e.g., removal of ovarian teratoma) may be curative.

Limbic encephalitis ^[15][16]

• Definition: inflammation of brain tissue that primarily affects the limbic system in the medial temporal lobes
• Pathophysiology: caused by an autoimmune reaction with antibodies directed against antigens richly expressed in the limbic system
• Etiology ^[19]
  • Most often paraneoplastic: associated with SCLC (most common), breast cancer, testicular cancer
  • Also associated with infections (e.g., HSV infection) and systemic autoimmune conditions (e.g., SLE, systemic sclerosis)
• Clinical features: similar to the general clinical features of encephalitis with prominent psychiatric and neurological manifestations
  • Severe short-term memory impairment
  • Seizures
  • Confusion
  • Psychiatric symptoms (e.g., depression, hallucinations, anxiety)
• Diagnosis: See “Diagnosis of encephalitis” for a structured approach to the workup of undifferentiated encephalitis.
  • Confirmatory test: characteristic autoantibodies (e.g., VGKC-complex antibodies, anti-AMPA receptor antibodies) ^[16]
  • CSF analysis: WBC > 5/mm³
  • Brain MRI: abnormalities in the bilateral medial temporal lobes
  • EEG: epileptogenic or slow-wave activity in the temporal lobes
  • Malignancy evaluation: e.g., CT chest to evaluate for SCLC
• Treatment
  • Immunomodulatory therapy (See “Treatment of autoimmune encephalitis.”)
  • Treatment of the underlying malignancy (e.g., treatment of lung cancer)